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Stem Cell Aging and Sex: Are We Missing Something?
Ben Dulken1,2,3 and Anne Brunet3,4,*
1Stanford
University Medical Scientist Training Program
Cell Biology and Regenerative Medicine Ph.D. Program
3Department of Genetics
4The Glenn Laboratories for the Biology of Aging
Stanford University, Stanford, CA 94305, USA
*Correspondence: [email protected]
http://dx.doi.org/10.1016/j.stem.2015.05.006
2Stem
Longevity differs between sexes, with females being longer-lived in most mammals, including humans.
One hallmark of aging is the functional decline of stem cells. Thus, a key question is whether the aging
of stem cells differs between males and females and whether this has consequences for disease and
lifespan.
A glance at the list of the human individuals currently living over the age
of 110—supercentenarians—reveals a
surefire strategy for achieving such
exceptional longevity: be female. Out
of the 53 living supercentenarians, 51
are female. No other demographic
factor comes remotely close to sex in
predicting the likelihood of achieving
such an advanced age. Sexual dimorphism with respect to longevity is a characteristic of most mammals and has
been recorded in human populations
since at least the mid-18th century. This
dichotomous capacity for resilience has
inspired wide-ranging hypotheses to
explain the underlying mechanisms. It
also raises questions regarding the sexual dimorphism of processes known to
sustain tissue regeneration and function
throughout life, including adult stem cell
renewal. Most adult stem cell populations undergo an age-related decline,
leading to dysfunctional tissue homeostasis, which most likely participates in
defining the ultimate lifespan of the
organism. Interestingly, sex-specific regulation of stem cell populations has
been demonstrated for several stem cell
types, and it has long been appreciated
that many canonical aging pathways
exhibit sex specificity. However, despite
the seeming interrelationship between
sex, stem cell maintenance, and aging,
few studies have sought to directly
explore the interaction of these three
variables. Here we discuss the sexual
dimorphism of adult stem cell populations and how processes regulating the
aging of stem cells may also be modified
by sex.
Sexual Dimorphism of Longevity
Hypotheses to explain the sexual imbalance in longevity have come from
divergent fields, including genetics,
evolutionary biology, and physiology.
One hypothesis is that the single X chromosome of males makes them functionally homozygous at all loci on that
chromosome, potentially rendering them
more susceptible to deleterious recessive traits. The maternal inheritance
of mitochondria could also result in sexual dimorphism in the function of mitochondria, which could in turn impact
metabolism and longevity. Evolutionary
hypotheses have postulated that the
sexes have adapted to be fit for different
needs—for example, females put more
investment in progeny production and
care than males in most species—and
that these different adaptive pressures
could result in antagonistic selection at
longevity associated loci. While these
genetic hypotheses are difficult to test
experimentally, the evolutionary forces
at play have resulted in differential
sex-associated phenotypes that may
determine lifespan. Most notably, the differential utilization of steroid hormones,
estrogen and testosterone (prominent
determinants of sex-specific phenotypes), has been proposed to contribute
to lifespan. Indeed, studies of human
eunuchs (castrated males) have shown
that their lifespan is about 14 years
longer than non-castrated males (Min
et al., 2012). Furthermore, supplementation with estrogen increases the lifespan
of male mice specifically (Fontana and
Partridge, 2015). However, the mechanisms by which estrogen and testos-
588 Cell Stem Cell 16, June 4, 2015 ª2015 Elsevier Inc.
terone modify lifespan have remained
elusive.
Stem Cells in Many Adult Niches Are
Regulated in a Sex-Specific Manner
The sex of an organism can modify the
behavior of its stem cell populations in a
way that may be adaptive. A recent study
has shown that hematopoietic stem cells
(HSCs) are more abundant and more proliferative in female mice than in male mice,
an effect that is dependent on estrogen
signaling (Nakada et al., 2014). The dependency on estrogen results in a further
increase in HSC number and proliferation
during pregnancy (Nakada et al., 2014).
A similar paradigm has been described
in neural stem cells (NSCs), where estrogen increases the proliferation of NSCs
in a transient manner that fluctuates
throughout the estrus cycle (Pawluski
et al., 2009). NSC proliferation is highest
during the proestrus phase of the estrus
cycle, when estrogen levels are particularly high. Exogenous administration of
estrogen is also sufficient to increase the
proliferation of NSCs in vivo (Pawluski
et al., 2009). In muscle, the resident stem
cells, termed satellite cells (SCs), exhibit
greater self-renewal and regenerative capacity in females than in their male counterparts (Deasy et al., 2007). Interestingly,
the enhanced regenerative capacity of female SCs does not appear to be related to
estrogen signaling as is observed in other
stem cell niches (Deasy et al., 2007), suggesting that estrogen signaling is not
the sole contributor to differences in
stem cell regulation between the sexes.
Other studies have shown that females
also exhibit increased capacity for rapid
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wound healing and liver
regeneration, processes that
are likely dependent on resident stem cell populations
(Deasy et al., 2007).
Thus, females tend to
exhibit increased stem cell
self-renewal,
regeneration
potential, and in some cases,
proliferation. However, the
question remains: does this
tendency toward increased
self-renewal in females alter
the capacity of stem cells to
regenerate tissues throughout aging, and does it influence longevity (Figure 1)?
particular case because the
aforementioned study used
only males, there is good
reason to believe that sex
may play a role. Estrogen
is known to induce the
expression of anti-oxidant
genes and reduce ROS,
while in contrast testosterone
increases oxidative stress.
Thus, DNA damage may be
bidirectionally regulated by
estrogen and testosterone
in an oxidative tug-of-war,
which may bear consequences for the health and
regenerative potential of
Figure 1. Potential Interactions between Stem Cells, Aging, and Sex
stem cells throughout the
Though interactions between stem cells, aging, and sex have been topics of
aging process.
The Ability of Stem Cells
great interest, the intersection of all three—the effect of sex on the aging of
stem cells—has not been well studied. However, several mechanisms could
Another potential mechato Regenerate Tissue
be involved in establishing and perpetuating sexual dimorphism during the
nism
involves the conserved
Declines with Age and
aging of stem cells.
‘‘pro-longevity’’ transcription
May Be Dependent
factor FOXO3. FOXO3 is inon Sex
Many stem cell niches experience a the environment of the stem cells. There hibited by insulin signaling and is necesdecline in self-renewal potential with age is undoubtedly a dearth of data address- sary for increased longevity in insulin
(Signer and Morrison, 2013). However, ing the differences in the aging of male signaling mutants (Signer and Morrison,
it is unclear whether age-associated and female stem cells, and this will likely 2013), a pathway that has a greater
impact on female than male lifespan (Fonchanges in stem cells differ between the be an active area for future investigation.
tana and Partridge, 2015). Moreover,
sexes. Interestingly, many canonical agFOXO3 has been shown to be vitally
ing pathways have been shown to have Potential Mechanisms Linking Stem
important for stem cell maintenance in
a sex-specific effect on lifespan. For Cell Aging and Sex
example, heterozygous knockout of insu- Though the sexual dimorphism of aging both HSCs and NSCs by preventing prelin-like growth factor type 1 receptor stem cells has been largely uncharacter- mature stem cell exhaustion (Signer and
(Igfr1) increases the lifespan of female ized, there are strong links between Morrison, 2013). Interestingly, FOXO3
mice only (Fontana and Partridge, 2015). sexually dimorphic characteristics— can interact with estrogen receptor
In contrast, transgenic overexpression of most notably the sex steroid hor- (ER-a) (Sisci et al., 2013). This interaction
Sirt6 increases the lifespan of male mice mones—and classical aging pathways is dependent on estrogen and profoundly
only (Fontana and Partridge, 2015). What known to be important for stem cell main- alters the cellular effects of FOXO3 (Sisci
are the effects of sexual differences in ag- tenance. These links suggest potential et al., 2013). These data suggest a fasciing pathways on stem cells? At this point mechanisms that may be involved in nating link between a known determinant
few studies have addressed this question. generating sex-dependent aging pheno- of stem cell maintenance during aging
and sex.
However, the limited work in this field types in stem cells (Figure 1).
A final prospective mechanism involves
does point to potentially fascinating differOne such mechanism is the sex-speences between the aging of male and fe- cific regulation of DNA damage and reac- telomerase, which is expressed by many
male stem cells. With regards to HSCs, a tive oxygen species (ROS). Several recent stem cell populations and is important
study of a pair of dizygotic twins—a studies have explored the role of DNA for their regenerative potential. Intrigumale and female—with hematopoietic damage and ROS accumulation in stem ingly, estrogen itself is capable of
chimerism demonstrated that in the male cell aging, processes which evidence activating telomerase directly through
environment, both genotypically male suggests may be modulated by sex. One ER-mediated transcription of TERT, the
and female HSCs had shorter telomeres such study demonstrated that, in muscle, protein component of the telomerase
as compared to the same cells in the fe- quiescent SCs accumulate DNA damage complex (Kyo et al., 1999). This hints at
male (Brüderlein et al., 2008). This finding with age (Sousa-Victor et al., 2014). The an intriguing mechanism by which cells
is consistent with the idea that a female accumulation of DNA damage over time in a female environment could delay the
organism provides an environment that in this stem cell population is associated aging process through the maintenance
is more conducive to sustained self- with irreversible senescence (Sousa- of telomeres.
While there are several tantalizing links
renewal. This study also suggests an Victor et al., 2014), suggesting that DNA
intriguing non-cell-autonomous mecha- damage accumulation can lead to loss between known mediators of aging stem
nism of differential aging patterns in of regenerative potential. While the influ- cells and sexual dimorphism, their relamale and female stem cells, mediated by ence of sex cannot be determined in this tionships need to be further explored.
Cell Stem Cell 16, June 4, 2015 ª2015 Elsevier Inc. 589
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This investigation may lead to new insights about the aging of stem cell populations and the sexual dimorphism of
lifespan.
Conclusions
Emerging evidence indicates that adult
stem cells in non-sexual tissues are regulated in a sexually dimorphic manner and
are responsive to sex hormones. Because
stem cell maintenance is important for
tissue regeneration throughout life, sexassociated differences in stem cell aging
may be associated with sexual dimorphism in lifespan. At this point, however,
very limited work has been done to
directly address this question.
So what does this mean for the field of
stem cell aging? At the very least it
should emphasize the importance of
controlling for sex in studies in which
age is a variable, as most recent work
in the field has done. However, beyond
that, it suggests a productive line of
investigation assessing the effects of
sex on the aging of stem cells. It will
also be important to understand how
sexual dimorphism in aging stem cells
predisposes individuals to sex-associated age-related pathologies such as
osteoporosis and cardiovascular disease. Furthermore, in any discussion of
aging, it is also important to consider
not only the lifespan, but also the portion
of healthy life or ‘‘healthspan’’ an individual experiences. It is likely that sex plays
a role in defining both lifespan and
healthspan, and the effects of sex may
not be identical for these two variables.
As the search continues for ways to
ameliorate the aging process and maintain the regenerative capacity of stem
cells, let us not forget one of the most
effective aging modifiers: sex.
Deasy, B.M., Lu, A., Tebbets, J.C., Feduska, J.M.,
Schugar, R.C., Pollett, J.B., Sun, B., Urish, K.L.,
Gharaibeh, B.M., Cao, B., et al. (2007). J. Cell
Biol. 177, 73–86.
Fontana, L., and Partridge, L. (2015). Cell 161,
106–118.
Kyo, S., Takakura, M., Kanaya, T., Zhuo, W., Fujimoto, K., Nishio, Y., Orimo, A., and Inoue, M.
(1999). Cancer Res. 59, 5917–5921.
Min, K.J., Lee, C.K., and Park, H.N. (2012). Curr.
Biol. 22, R792–R793.
Nakada, D., Oguro, H., Levi, B.P., Ryan, N., Kitano,
A., Saitoh, Y., Takeichi, M., Wendt, G.R., and Morrison, S.J. (2014). Nature 505, 555–558.
Pawluski, J.L., Brummelte, S., Barha, C.K.,
Crozier, T.M., and Galea, L.A. (2009). Front. Neuroendocrinol. 30, 343–357.
Signer, R.A.J., and Morrison, S.J. (2013). Cell Stem
Cell 12, 152–165.
REFERENCES
Sisci, D., Maris, P., Cesario, M.G., Anselmo, W.,
Coroniti, R., Trombino, G.E., Romeo, F., Ferraro,
A., Lanzino, M., Aquila, S., et al. (2013). Cell Cycle
12, 3405–3420.
Brüderlein, S., Müller, K., Melzner, J., Högel, J.,
Wiegand, P., and Möller, P. (2008). Aging Cell 7,
663–666.
Sousa-Victor, P., Gutarra, S., Garcı́a-Prat, L.,
Rodriguez-Ubreva, J., Ortet, L., Ruiz-Bonilla, V.,
Jardı́, M., Ballestar, E., González, S., Serrano,
A.L., et al. (2014). Nature 506, 316–321.
590 Cell Stem Cell 16, June 4, 2015 ª2015 Elsevier Inc.